Sulfonyloxy bromoacetanilides and their utility as biocides

ABSTRACT

SULFONYLOXY BROMOACETANILIDES AS NEW COMPOSITIONS AND THEIR ACTIVITY AS MICROBIOCIDES. REPRESENTATIVE COMPOUNDS INCLUDE M-ISOBUTYLSULFONYLOXY BROMOACETANILIDE AND M-PHENYLSULFONYLLOXY BROMOACETANILIDE.

United States Patent 3,836,564 SULFONYLOXY BROMOACETANILIDES AND THEIRUTILITY AS BIOCIDES Don R. Baker, Orinda, and Eugene G. Teach, ElCerrito,

Calif., assignors to Staulfer Chemical Company, Westport, Conn.

No Drawing. Continuation-impart of application Ser. No.

127,775, Mar. 24, 1971, which is a division of application Ser. No.806,717, Mar. 12, 1969, both now abandoned. This application Sept. 11,1972, Ser. No.

Int. Cl. C07c 143/02 US. Cl. 260-456 A 3 Claims ABSTRACT OF THEDISCLOSURE Sulfonyloxy bromoacetanilides as new compositions and theiractivity as microbiocides. Representative compounds includem-isobutylsulfonyloxy bromoacetanilide and m-phenylsulfonyloxybromoacetanilide.

wherein R is hydrogen or lower alkyl having from 1 to about 4 carbonatoms, inclusive, R represents (1) hydrogen;

ii CN RX in which 'R and R are independently hydrogen, alkyl, allyl,lower alkoxyalkyl, cyclohexyl, 2-chloroallyl, phenyl, benzyl, orsubstituted-phenyl in which the substituents are chloro, nitro, loweralkyl, lower alkoxy or cyano, R and R taken together represents analkylene containing 4 to 6 carbon atoms, inclusive, or loweralkylsubstituted alkylene containing a total of to 8 carbon atoms,inclusive; I

in which R is alkyl, phenyl, substituted-phenyl in which thesubstituents are chloro, nitro, lower alkyl, lower alkoxy or cyano;

(I? 4) -C-ORB in which R is alkyl, phenyl, substituted-phenyl in whichthe substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano;

ice

in which R is hydrogen, alkyl, haloalkyl, phenyl, substituted phenyl inwhich the substituents are chloro, nitro, lower alkyl, lower alkoxy orcyano; provided that when R is hydrogen and R is hydrogen, then thegroup is substituted in the meta-position; and provided that when R isis in the meta-position. The above compounds as well as compounds inwhich R is hydrogen and R is hydrogen and is in the para-position, areeffective microbiocides.

In the above description, the following preferred embodiments areintended for the various groups. Alkyl preferably includes, unlessotherwise provided for, those members which contain from 1 to about 6carbon atoms, inclusive, in both straight chain and branched chainconfigurations, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec.-butyl, amyl, isoamyl, n-hexyl, isohexyl, and the like; andlower alkoxyalkyl preferably includes those members which contain atotal of not more than 6 carbon atoms, for example, methoxymethyl,methoxyethyl, ethoxymethyl, methoxypropyl, ethoxypropyl, propoxypropyl,ethoxybutyl, methoxyamyl, and the like. Haloalkyl preferably includesthose alkyl members which contain from 1 to about 4 carbon atoms,inclusive, and are substituted with at least one halogen such aschlorine, bromine and iodine. Lower alkyl and lower alkoxy preferablyinclude those members which contain from 1 to about 4 carbon atoms,inclusive, in either straight chain or branched chain configurations.

The compounds herein described can be prepared by one of severalmethods, depending upon the nature of the starting materials andproducts desired. The compound '-hydroxybromoacetanilide within thescope of thi invention can be conveniently prepared by the condensationof m-aminophenol and bromoacetyl bromide. This preparation isspecifically described in Example I below. Starting with either the 3 or4' hydrobromoacetanilide, subsequent condensation reactions can beperformed which will ultimately yield other members of this series.Generally, these reactions are performed in a suitable solvent, such asbenzene, toluene, acetone, methylethyl ketone and the like. Themonosubstituted carbamate condensation reactions are carried outemploying the appropriate isocyanate in the presence of catalysts, suchas triethylene diamine and dibutyltin dilaurate, in order to facilitatethe completion of the reaction. Alternatively, the carbamate derivativesdisclosed herein, preferably when R and R are both hydrogen, areprepared by conversion of the substituted-phenol to the correspondingchloroformate using phosgene, followed by reaction with the appropriateprimary or secondary amine or ammonia. The preparation of the sulfonate,dialkyl carbamate, carbonate and carboxylate derivatives are preparedusing the appropriate acid halide and an acid acceptor such as pyridene,triethylamine, sodium bicarbonate and the like. After the reaction iscompleted, the solvent is removed and the product recovered therefrom.Upon isolation of the crude product, final recovery of the purifiedmaterial is accomplished by normal workup procedures, such ascrystallization or distillation.

It has been found that the compounds as defined supra are effectivebacteriostatic and fungistatic agents. Whereas microbiological growthson various substances cause deterioration by the presence of theinfestation, the application of an agent to retard this adverse growthis desired. Such substances liable to fungus and bacterial infectioninclude cloth, leather, paint, soaps, paper, wood, plastic, oil, and thelike. It is contemplated herein that the microbiocidal compositions ofthe present invention may be effectively incorporated or applied to anyof the substances susceptible to microbiological growths.

For maximum effectiveness, the active ingredients of the presentinvention are admixed in microbiostatically effective amounts which aninert adjuvant. In order to provide formulations particularly adaptedfor ready and efficient application to the materials to be treated, suchformulations comprise those of both the liquid and solid types as wellas the aerosol type formulations. Application can be directly to thesubstance to be protected from fungus and bacterial growth. In the purestate, the active ingredient may be too effective or too potent in someapplications to have practical utility. A convenient method of treatingcloth is by formulating the active ingredient with a soap or detergentand thereby imparting antiseptic or microbiocidal properties to thecloth as it is washed therewith.

For most effective protection it is preferred to apply the materials inintimate contact but thoroughly dispersed on or nearly in the surface tobe protected. Therefore, the active ingredients have incorporatedtherewith a relatively inert agent or adjuvant as a dispersing medium,utilizing methods well known to those skilled in the art.

Suitable formulations of the compounds of this invention comprise theabove-defined active ingredients and a suitable material as an adjuvanttherefor. Fungistat and bacteriostat compositions are advantageouslyformulated by first preparing a solution thereof in an organic solventand then adding the resulting solution to water or other carrier. Ifnecessary, an emulsifying agent may be employed. The compositions mayalso be incorporated into solid carriers such as clay, talc, pumice,soap, and the like. They may also be dissolved in liquefied gases suchas fluorochloroethanes or methyl chloride and applied from aerosol bombscontaining the solution. It should be noted that suitable formulationsmay also include adhesive agents, indicators, and other microbiocidalingredients. Other ingredients may be supplementary insecticides,fungicides, bacteriocides, nematocides or selective herbicides.

Since the amount of active agent of the present invention which isemployed will vary with the microbiocidal effect sought, the utility ofthe treated material, type and dimensions of the material treated, it isevident that no rigid limits can be set forth on the quantity required.Determination of the optimum effective concentration for a specificperformance is readily ascertainable by routine procedures, as will beapparent to those skilled in the art.

Preparation of the compounds of the present invention are illustrated bythe following particular examples. Following the examples is a table ofcompounds which are prepared according to the procedures describedherein.

4 EXAMPLE I Preparation of 3'-hydroxybromoacetanilide m-Aminophenol,66.5 g. (0.61 mole), is dissolved in 500 ml. of a 50/50 (v./v.) mixtureof glacial acetic acid and saturated sodium acetate solution. 'Ihemixture is cooled to approximately 10 C. and 200 g. (0.99 mole) ofbromoacetyl bromide is added dropwise. The temperature is maintainedbetween 15 and 20 C. When addition is complete, the mixture is stirredwhile cooling until the temperature is about 5 C. The product isfiltered off, washed successively with cold water, saturated sodiumbicarbonate solution and finally two portions of water. The product isdried under vacuum. The yield of the title compound is 121 g. (86percent of theory), mp. 167- 170 C.

EXAMPLE II Preparation of 3-Nmethyl car-bamoyloxy bromoacetanilide3-hydroxybromoacetanilide, 34.5 g. (0.15 mole) in 250 ml. of acetonecontaining approximately mg. of triethylene diamine and 5 drops ofdibutyltin dilaurate is refluxed for two hours with 9.4 g. (0.165 mole)of methyl isocyanate. On cooling, the product crystallizes from solutionand is recovered by filtration. There is obtained 24 g. (56 percent oftheory) of the title compound, mp. 136-138 C.

EXAMPLE III Preparation of m-Isobutylsulfonyloxy bromoacetanilide To3'-aminophenyl isobutyl sulfonate, 6.9 g. in 100 ml. of methylenechloride is added 6.1 g. of bromoacetyl bromide. The resulting solutionis cooled and 3.1 g. of triethylamine is added dropwise. The product isrecovered by washing with cold water, drying and removal of the solvent.There is obtained 8.9 g. of the title compound, n =1.5500-.

EXAMPLE IV Preparation of m-Phenylsulfonyloxy bromoacetanilide To amixture of 4.4 g. of benzene sufonyl chloride and 5.7 g. of 3'-hydroxybromoacetanilide in 100 ml. of methylene chloride is added dropwise 2.6g. of triethylamine. The product is recovered by washing with coldwater, dryiug and removal of the solvent. There is obtained 9.0 g. ofthe title compound, n =1.583O.

TABLE I C-CH2B1 Compound M.P. C. number R1 R2 Position or n0 H 167-170C(O)NHCH3 do 136-138 C(O)NHCH(CH3)2 -do 144-149 C(O)NHCH2OH=CH:..--- 10-122-125 C(O)NH(cyc1ohexyl) do 163-165 H Para 1 11-144 7 S(Oz) l-C4HsMEti1 1. 5500 8 S(O2)phenyl do l. 5830 Other examples of compoundsfalling within the generic formula presented herein, which arepreparable by the aforedescribed procedures and which may be formulatedinto microbiocidal compositions and applied as herein illustrated, are:

Compound number R1 R2 Position H Meta. C (O)NH2 D0. C NHCHs D0.C(O)N(GHZ%)2 Do. C(O)NHnC.1Ho Do. (0)N(nCiHr)2 Do. O(O)NH1 Do. C (O) NHCH3 D o. C(O)N(CH3)2 Do. C O)N(n-C Ho 2 D0. C(O)N(CH2CH==CH2)2 Do.)N=(CH2)e D0. 0 (O)NH(phenyl) Do. C (O)NH(phenyl) Do. C(O)NH(CHCH OCH1)Do. 0 (O)NH(CH2CH2O C2H5) Do. C (O)NH (benzyl) Do. 0 (O)NH(benzyl) Do.C(O)NH(CH CCl::CH2) Do. C(O)NH(CH2CC1=CH2) Do. C (O)NH(p-NOr-phenyl) Do.C (O)NH(p-NOz-phenyl) Do. C (O) NH (p-Cl-phenyl) Do. C(O)NH(m-Cl-phenyll Do.

Do. 0 N

34 CzHs D0.

C (O) N H 8(02) CH3 Para. CzHs S(O2) C 11 lVIeta. H C (O) 0 CH3 D o.

C(O)OCHs Para. C2 5 C(O)OCHs D0. C2115 C(O)OCH: Meta. Z B (O)O 2 5 Para.H C (0)0Cz1'15 Meta. H C(O)H D0: H C (0)11 Para. C2115 C(O)H lvleta.02H; C(O)H Para. C(O)C2Hs Meta. CzHa C(O)Cz 5 D0. C2 s C (0) CH3 Para.CzHs S(O2)phenyl Meta.

S(O2)(p-G1-phenyl) Do; 02H; S(O2) (m-Cl-phenyl) Para. H S(O2)(m-NOz-phenyl) Meta. H 5(02) (GH3-pheny1) Do. H S(O2)(1 -CH3O-phenyl)Do. i-C3H1 8(02) (p-CN-phenyl) Do. S(O2) (p-Br-phenyl Do. C(O)O-phenylDo. 1-C H1 0(0) 0 ('p-Cl-phenyl) Para. H C (0)0 (mNOZ-phenyl) Meta. CH30 (0) O (p-CHg-phenyl) Do. 11 C (0)0 (p-CHzO-phenyl) Meta. CH; C (O) O(o-Olil -phenyl) Para. 02H; C (0)0 (p-ON-phenyl) Dc. H C(O)CH2Br Meta.CH; C (O) CHzCHzCl D0. H C (O)-p-Cl-phenyl Para. CH0 C(O)-m-NOz-phenylMeta. 02H: C (O) -p-CHa-phenyl Para.

C (O)-pCH O-phenyl D0. CH; C (0)p-CN-phenyl Meta. H C (0)-phenyl Do.02115 C (O)-phenyl Do. C2Hs C (O)N H(cyc1ohexyl) Para. H C(O)NH(p-ON-phenyl) Meta. n-CrHr C (O)NH(pCN-phenyl) Do. H C(O)NH(p-CH3O'phenyl) Para. H C(O)NH(p-CHiOphenyl) lvlela. CH3C(0)NH(o-CH3-phenyl) Do.

As previously mentioned, the herein described compounds aremicrobiostatic agents which are useful and valuable in controlling fungiand bacteria. The compounds of this invention are tested asmicrobiocides in the following manner.

In Vitro Vial Tests. The compounds are tested to determine themicrobiostatic efficacy when in contact with lus niger andPenicilliumitalicum, and cells of the bacteria, Escherichia coli andStaphylococcus aureus, are inoculated into the vials containing nutrientbroth (one specie of organism per vial). The vials are then sealed andheld for one week, after which time the growth of the organisms isobserved and noted. The tests are repeated using lower concentrations ofthe candidate compounds to determine the lowest concentration that canbe used and still offer some control of the growth of the organism.Table II shows the results of the in Vitro tests.

TAB LE II In vitro test lowest efiective concentration (p.p .m.)

Compound Aspergillus Penicilliam Escherichia Staphylococnumber nigeritalic'am c 1' car aureus N orn. =Indicates partial control at thisconcentration; A=Chloro/ ilglftg of Compound Number 1; B=Chlorolanalogof Compound Num- Microbiocide Testing Procedure Using Agar. This testmeasures the bactericidal and fungicidal properties of a compound whenin contact with a growing bacterium or fungi in an artificial medium.The test is conducted by adding 20 ml. portions of a suitable warmsterile agar solution into 20 x 100 mm. petri dishes. Then, the testcompound, in 0.5% acetone solution, is added to the petri dishes atlevels of 0.5, 1, 10, 50 and 100 ,ag./ml. and mixed with the warm mobileagar solution. The treated agar mixture is then allowed to come to roomtemperature and solidify. Cells of the particular organism are thenstreaked on the surface of the solidified agar and are then incubatedfor such lengths of time that untreated samples containing no toxicantshow luxurious growth typical of the particular organism. This timevaries from 24 hours to one week, depending on the particular organism.The fungi are incubated at 30 C. and the bacteria are incubated at 37 C.Nutrient agar is used as the medium in this test for the bacteria.Potato dextrose agar is used as the medium for the fungi. The tablebelow shows the results when sulfonyloxy bromoacetanilides are employedin this test.

TABLE III Microbioeidal activity in ages;g inhibitory concentration SoapPlug Test. Samples of Compounds No. 1 and 3, and3,4,4-trichlorocarbanilide (TCC) are incorporated at a level of 1% insodium stearate using acetone with the slurry. The products are airdried and pressed in a metal tube to form a soap plug approximately 10mm. in diameter and 2 mm. thick. These are placed on nutrient agarplates that have been streaked separately with Escherichia coli andStaphylococcus aureaus cells. The plates are incubated at 37 C. for 17hours. The radius of the zone of biological inhibition around the soapplug is measured. The data from this test are as follows:

TABLE IV Soap plug test Zone of biological inhibition (mm.)

Detergent Formulation Test. Samples of Compounds No. 1 and 3 of 1020 mg.are dissolved in 5 ml. of acetone and added to weighed amounts of acommercial laundry detergent identified as Tide, a trademark owned byProcter and Gamble (a mixture of lauryl sulfate and alkylbenzenesulfonate with tripolyphosphate as a binder), to give aconcentration of 0.2% in the detergent. From these detergent samples, 1g. is added to 500 m1. of 50 C. tap water. To this wash solution isadded 25 g. of laundered white cotton duck and the mixture agitated bystirring for minutes. The cloth samples are hand wrung and each sampletwice rinsed with stirring for 10 minutes in 500 m1. of 50 C. tap water.Thereafter, the cloth samples are hand wrung and air dried. Samples (1square approximately) of the treated cloth samples are placed onnutrient agar plates that have been separately streaked withStaphylococcus aureus, Escherichia coli, Brevibacterium. ammoniagenes,and T richophyton mentagrophytes.

The following controls are included in this test: A blank and a controlcontaining a commercial laundry detergent identified as Dreft, atrademark owned by Procter and Gamble (active ingredients are sodiumdoderyl-benzene sulfonate, sodium perborate), which contains the biocide3,3,4-trichlorocarbanilide (TCC). The plates are incubated at 37 C. forvarious lengths of time to provide growth for the organisms at whichtime the zone of biological inhibition around the cloth samples ismeasured. The radius of the zone of biological inhibition around thecloth samples are reported in the following Table V.

8 What is claimed is: 1. A compound having the formula wherein R ishydrogen or lower alkyl having from 1 to 4 carbon atoms, inclusive, Rrepresents is in the meta-position.

3. A compound according to Claim 2 in which R is isobutyl.

References Cited UNITED STATES PATENTS 3,032,555 5/1962 Oxley et a1.260456 A X 3,687,998 8/1972 Trepka 260456 A 3,271,451 9/1966 Tishler eta1. 260456 A X 2,289,805 7/1942 Porter et a1. 260-456 A X HOWARD T.MARS, Primary Examiner N. P. MORGENSTERN, Assistant Examiner U.S. Cl.X.R.

260239 B, 293.74, 326.3, 456 R, 456 P, 463, 465 P, 468 E, 469, 471 R,473 R, 479 C, 487, 488 CD, 562 A, 562 B; 424-267,274, 286, 300, 301,303, 304, 308, 309, 3H, 320

